Although effective anticancer drugs have high specificity and activity against cancers, most drugs distribute throughout the body and are toxic to neoplastic cells. This dose-limiting toxicity associated with most anticancer drugs constrains their potential therapeutic efficacy, therapeutic efficacy. To minimize adverse effects from higher dosages, drugs can be delivered by formulating them as targetable carriers to increase the concentration at the target site and decrease drug concentrations elsewhere in the body or by giving local/intratumor/peritumor injection.
Hyaluronan has been reported to be an ideal carrier for localizing anticancer drugs. Hyaluronan (HA) is a polysaccharide, of alternating D-glucuronic acid and N-acetyl D-glucosamine, found in the connective tissues of the body and cleared primarily by the lymphatic system (12 to 72 h turnover half-life). Gibbs et al. reported that HA-Irinotecan containing standard doses of irinotecan could be safely administered to patients by infusion through a peripheral vein over 90 min. Comparison to historical irinotecan data suggests HA-Irinotecan may have a greater margin of safety without compromising anticancer activity (P. Gibbs, T. J. Brown, R. Ng, R. Jennens, E. Cinc, M. Pho, M. Michael, R. M. Fox, A pilot human evaluation of a formulation of irinotecan and hyaluronic acid in 5-fluorouracil-refractory metastatic colorectal cancer patients, Chemotherapy, 55 (2009) 49-59). Cai et al. also reported that the hyaluronan-doxorubicin nanoconjugate administered subcutaneously 2-3 mm from the tumor margins reduces dose-limiting cardiac toxicity with minimal toxicity observed in normal tissues and dramatically inhibits breast cancer progression in vivo, leading to an increased survival rate. Thus, localized chemotherapy to the breast lymphatics with this nanocarrier may represent an improved strategy for treatment of early stage breast cancers (S. Cai, S. Thati, T. R. Baghy, H. M. Diab, N. M. Davies, M. S. Cohen, M. L., Forrest, Localized doxorubicin chemotherapy with a biopolymeric nanocarrier improves survival and reduces toxicity in xenografts of human breast cancer, Journal of controlled release: official journal of the Controlled Release Society, 146 (2010) 212-218).
Injection of thermal reversible hydrogel will lead to the formation of a “depot” at the site of administration that slowly and continuously releases the drug to the tumor and surrounding tissue. This kind of topical or injectable gel for physical targeting has additional advantages over passive or other actively targeted therapies in that it can deliver a drug throughout the tumor regardless of vascular status, thus providing accurate dosing without systemic toxicity. Poloxamer gels have been widely applied in drug delivery since they are relatively easy to manufacture and already widely employed in the pharmaceutical fields as “generally regarded as safe” (GRAS) excipients. Currently, research on this type of thermosensitive hydrogels mainly focuses on poloxamer 407 (Pluronic F-127, Molecular Probes, Inc., Eugene, Oreg.). For localized cancer therapy, intratumoral, peritumoreal, and intravesical injection of thermal sensitive hydrogel composed of Pluronic® F127 (F127) has been proposed (Y. L. Lo, C. Y. Hsu, H. R. Lin, pH-and thereto-sensitive pluronic/poly(acrylic acid) in situ hydrogels for sustained release of an anticancer drug, J Drug Target, 21 (2013) 54-66). However, such poloxamer gels for drug delivery applications have substantial drawbacks including the gelation time being too long, limited stability, poor mechanical properties and short residence times due to rapid dissolution once placed in a biological environment.
US 20120100103 relates to an situ-forming injectable hydrogel comprising two or more homogeneous or heterogeneous polymers, which are bonded to each other by a dehydrogenation reaction between phenol or aniline moieties on adjacent polymers. US 20140065226 provides compositions including a thereto-responsive hydrogel and a biocompatible monomer or polymer including an amino acid side chain (i.e., having an amino acid linked to the remainder of the monomer or polymer through its side chain), which has thermo-responsive behavior at physiological temperature and is useful as injectable and topical formulations, particularly for biomedical applications such as localized drug delivery.
Although several thermosensitive injectable hydrogels have been developed, there are no satisfactory thermosensitive injectable hydrogels for localized therapy. Therefore, there is a need for developing an in situ forming hydrogel with superior effects in therapy.